Pursuant to our interest in the cellular interactions which occur during immune responses, it is proposed to analyze the mode of action of soluble factors which are active in promoting specific events in triggering T cell proliferation and differentiation. Elucidation of the means by which soluble factors accomplish cell-cell communication will yield novel avenues for therapeutic manipulation of the level and quality of immune responses, for treatment of a variety of disease states. The proposed research has the following specific objectives: (1). To determine the role of the products of non-T """"""""accessory cells"""""""" (macrophages or dendritic cells) in promoting responsiveness of resting T cells to the T cell growth factor (IL-2); a requirement for an accessory cell factor in this process has been detected in preliminary experiments. The factor will be compared to another accessory cell product (IL-1), and it will be directly determined whether it stimulates the expression of IL-2 receptors on T cells. (2) To functionally characterize the role of a novel T cell derived lymphokine activity, distinct from IL-1 and IL-2, which has been detected in preliminary experiments. As the lymphokine stimulates production of IL-2 by enriched populations of normal T cells, it is likely to serve an important role in T cell activation. Purified normal T cells and cloned T cells will be used to determine the interrelationship of the novel lymphokine and IL-1, and its specific role in stimulating IL-2 production. (3) Maturation of effector CTL requires a differentiation factor distinct from IL-1 and IL-2, which is currently being purified in this laboratory. It is proposed to use purified differentiation factor and purified samples of the other factors (Aims 1,2) to systematically define the required factors for stimulation of T cell proliferation and maturation (to CTL). The approach will involve the use of highly purified T cell populations cultured at progessively lower cell densities, so as to enable us to detect any heretofore undetected factor requirements. (4) The role of purified factors in stimulating cell cycle transitions of resting T cells will be systematically evaluated.
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